Significance/Aims. The b3-adrenoceptor is located on brown and white adipose tissue, and has been implicated in the regulation of energy expenditure and fat metabolism. A polymorphism (codon 64 TGGTrp --> CGGArg; Trp64Arg) of the b3-adrenergic receptor gene, with an allelic frequency of 0.08 in Caucasians, has been identified. Cross-sectional studies demonstrate that individuals with this Trp64Arg polymorphism have a greater body mass index, earlier onset of type II diabetes, and a tendency for a lower resting metabolic rate, although these results are equivocal. Nevertheless, preliminary data implicate the Trp64Arg polymorphism in the regulation of energy expenditure and body composition. Changes in energy expenditure and body composition with aging are highly variable. To our knowledge, no longitudinal studies have examined changes in energy expenditure and body composition in older women and men with the Trp64Arg polymorphism. A Trp64Arg polymorphism of the b3-adrenoceptor may partially explain the heterogeneity of age-related changes in energy expenditure and body composition in older women and men. I hypothesize that older individuals with the Trp64Arg polymorphism will have a greater decline in energy expenditure, and increase in total and central body fatness over time compared to normal homozygotes. Understanding the role of this polymorphism on rates of aging is important since alterations in energy expenditure and body composition in older individuals are associated with increased risk of cardiovascular disease and associated comorbidities such as hypertension, type II diabetes, and certain forms of cancer. Approach. During the past 4 to 10 y, we have tested 434 Caucasian women and men over the age of 40 y in our laboratory for resting metabolic rate using indirect calorimetry, body composition via underwater weighing and dual energy x-ray absorptiometry, waist circumference for central adiposity, treadmill aerobic fitness, and various cardiovascular risk factors (i.e., cholesterol, HDL, insulin, blood pressure). Additionally, 90 of these individuals were assessed for total daily energy expenditure data using doubly labeled water. We will genotype these older individuals using allele specific oligonucleotide hybridization and retest them to examine whether energy expenditure and body composition vary with aging between individuals with the Trp64Arg polymorphism and normal homozygotes. This proposal represents a unique combination of molecular biology and clinical physiology to longitudinally examine phenotypic consequences of a recently discovered genetic polymorphism, that may predispose individuals to low energy expenditure and weight gain.